PET scans show areas of high FDG (glucose) uptake in an individual before (pink outline) and after (blue outline) receiving antiretroviral therapy for HIV infection. In the second image, the spike in sugar-hungry cells corresponds to a diagnosis of immune reconstitution syndrome, or IRIS. (Credit: NIAID)

In people living with HIV, antiretroviral therapy (ART) can suppress viral replication, improve overall health and normalize life expectancy. Unfortunately, some people treated with ART after HIV has already significantly damaged the immune system -- particularly those with opportunistic infections such as tuberculosis or cytomegalovirus -- may develop a serious condition called HIV-associated immune reconstitution syndrome (IRIS). In people with IRIS, the rebounding immune system overcompensates for HIV-associated damage with severe inflammation that can damage tissues and cause symptoms such as high fevers. Now, infectious-disease and radiology researchers from NIAID and the NIH Clinical Center are working together to visualize and predict this common complication of HIV in a new way -- with positron emission tomography (PET). The researchers describe their findings in a paper published this week in Clinical Infectious Diseases and in a new NIAID Video SNiP.

The study began when researchers led by Irini Sereti, M.D., chief of the HIV Pathogenesis Section of the NIAID Laboratory of Immunoregulation, discovered that immune cells reactivated by ART in people with IRIS were more likely to express a cellular receptor called Glut-1. This receptor helps cells take in glucose, the sugar they use to fuel their overactive inflammatory response. Glut-1 also recognizes 18F-Fluorodeoxyglucose (FDG) -- a tracer PET molecule used to quantify cellular sugar metabolism. FDG PET scans are commonly used to visualize tumors that require excessive amounts of energy as they increase in size. While Dr. Sereti and her team could track the inflammatory response of IRIS by looking at patient's blood samples, they wondered if they could also visualize this disease process in action with PET. To help answer that question, they collaborated with Dima A. Hammoud, M.D., a tenure-track investigator and chief of the Hammoud Laboratory at the Center for Infectious Disease Imaging in the NIH Clinical Center.

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Together, Drs. Sereti and Hammoud recruited 30 volunteers with untreated HIV and opportunistic infections that put them at an elevated risk for developing IRIS. Dr. Hammoud and her team acquired whole-body FDG PET scans of each patient just before beginning ART and four to eight weeks later. Based on their symptoms and measurements of inflammatory biomarkers in their blood, 10 patients developed IRIS. Using advanced methods to measure FDG uptake, Dr. Hammoud found that the post-treatment PET scans of these patients generally showed an increase in tissue FDG uptake compared to the scans taken before they began ART -- indicating an increased need for energy and, therefore, the immune reactivation that defines IRIS. Patients who did not develop IRIS -- and did not require that extra energy for their immune cells -- generally showed a decrease in FDG uptake on their post-treatment PET scans.

Furthermore, the researchers found that participants who developed IRIS had greater metabolic activity during their first PET scan than those who did not. This finding, Drs. Sereti and Hammoud explained, may mean that PET scans could be used to more accurately predict who will develop IRIS, and that could help physicians make decisions about when to begin ART in people with opportunistic infections and low numbers of CD4+ T cells, a measure of immune system health. The researchers also noted that the pre-treatment PET scans unexpectedly detected "hot spots" of viral activity in the spleen and bone marrow -- areas not usually known to harbor significant reservoirs of HIV or immune responses to the virus. PET, the study authors suggest, may be a way to further explore the role of these tissues in HIV-related inflammation.

Learn more and see the PET scanner in action by watching the NIAID Video SNiP below:

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